The long-term goal of this proposal is to understand molecular mechanisms of bone resorption, a process that requires osteoclast (OC) differentiation and activation, and is altered in multiple bone disorders such as osteopetrosis and osteoporosis. OC differentiation is regulated by several factors, including M-CSF (macrophage-colony stimulating factor) and RANKL (receptor activator of NF-kB ligand). OC activation is initiated by cell adhesion to the bone surface. Although molecular mechanisms of OC differentiation and activation have been extensively studied, modulation of these processes in bone loss-associated diseases (e.g., diabetes) remains largely unknown. The receptor for advanced glycation end products (RAGE), a member of the immunoglobin superfamily of cell surface receptors, has been implicated in the pathogenesis of age-related and/or bone loss-associated disorders, including diabetic complications, neurodegeneration, and inflammatory disorders. The link between RAGE and these pathologic situations is the multi-ligand character of the receptor and its ability to induce sustained cellular activation. Ligands of RAGE include (but are not limited to) diabetes-associated AGEs (advanced glycation endproducts) and proinflammatory cytokines of the S100 family and HMGB1. In preliminary studies, we present evidence for a role of RAGE and its ligand HMGB1 in OC differentiation and function with consequences for bone remodeling. Based on our preliminary results and in light of a potential role of RAGE in age-associated bone loss, we hypothesize that HMGB1-RAGE signaling is involved in RANKL induced OC differentiation and function, contributing to bone-loss associated disorders, such as diabetes. Three aims are proposed to test this hypothesis. Aim 1. To investigate mechanisms by which RAGE regulates OC maturation and function. Aim 2. To further investigate the role of HMGB1, as an autocrine ligand of RAGE, in the regulating OC differentiation and function. Aim 3. To determine the role of RAGE in diabetes-associated bone loss. Our ability to test this hypothsis is facilitated by access to RAGE mutant mice and innovative collaboration among experts in RAGE signaling transduction and osteoclast biology at MCG.